SCN5A Variant I925F Detail

We estimate the penetrance of LQTS for SCN5A I925F around 5% and the Brugada syndrome penetrance around 10%. SCN5A I925F was found in a total of 1 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. I925F is present in 1 alleles in gnomAD. I925F has been functionally characterized in 0 papers. This residue is located in a Mild_Hotspot region for Brugada syndrome and a Non_Hotspot region for LQTS. In silico predictions, functional data (if available), and location in structure are equivalent to phenotyping 10 individuals for Brugada syndrome (1 diagnosed with Brugada syndrome) and 5 individuals for LQTS (0 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A I925F around 5% (0/11) and the Brugada syndrome penetrance around 10% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-3.08 0.062 4.66 0.901 13 2
PROVEAN scores less than -2 are considered deleterious. REVEL scores higher than 0.5 or 0.75 are considered likely pathogenic (higher sensitivity with the former cutoff, higher specificity with the latter cutoff). A PolyPhen-2 score of 0.85 or greater is considered likely pathogenic. BLAST-PSSM reflects the evolutionary conservation of residue substitutions, more negative numbers indicate fewer observations of the specific substitution than is expected. Penetrance Density is our previously published method to calculate the average BrS/LQTS probability density in a shell of residues surrounding a residue of interest (Kroncke et al. 2019).

Reported Carrier Data

PubMed ID Year Carriers Unaffected LQT3 BrS1 Other Other Disease
LITERATURE, COHORT, AND GNOMAD: - 1 1 0 0 -
VARIANT FEATURES ALONE: - 15 14 0 1 - -
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts. We do not distinguish here between multiple missense codons. Missense variants are combined across degenerate codon substitutions since codon-level data were not consistently available for curation.

I925F has 66 previously observed neighbors within 15 angstroms

A residue within a folded protein on average has nearest neighbors that fall roughly into two shells: a "nearest" neighbor around 5-6 angstroms and a second shell around 11 angstroms. All variants shown in the rightmost column have been observed in at least one individual in the literature or gnomAD.

Neighbor Distance (Angstroms) Variants Observed in Individuals
891 11 I891N, I891T,
848 12 I848F,
856 13 V856L,
919 11
896 13 C896S,
895 9 L895F,
842 13
249 15 K249X,
894 11 I894M,
247 8 V247L,
240 12 V240M,
254 13
926 4
250 11
409 14 L409P, L409V,
928 7 L928P,
925 0 I925F,
227 12 L227P,
366 14
934 14
933 11
246 10
851 14 c.2550_2551dupGT, F851L, p.F851CfsX19, c.2552_2553dupGT,
412 12 V412D,
897 13 G897E, G897R,
924 4 V924I,
927 8 N927S, N927K,
852 11
854 13 c.2559delT,
245 14 Q245K,
224 14 L224F,
845 11 c.2533delG,
244 11
892 14 F892I,
849 7
226 15 A226G, A226V,
921 6
922 6 V922I,
405 14
248 13
241 13
920 9
843 14 T843A,
930 7 c.2788-6C>T, c.2787+17_2787+18insACACACACACACACACACACACA,
1459 15 c.4376_4379delTCTT,
918 10
917 12 L917R, L917V,
239 13 I239V , I239V,
230 14 I230M, I230T, I230V,
251 14
916 14
242 12 A242D,
929 6
408 12
253 15
847 12
846 9 L846R,
853 8
370 14 T370M,
923 8
899 13
850 10 V850M, c.2549_2550insTG,
411 14 V411M,
243 8
932 11
931 10